The following abbreviations are used throughout the following specification and in the claims:
IL-1=Interleukin-1 PA0 CSF=Colony Stimulating Factor PA0 G-CSF=Granulocyte Colony Stimulating Factor PA0 GM-CSF=Granulocyte Macrophage Colony Stimulating Factor PA0 LPS=Bacterial Lipopolysacharide PA0 TNF=Tumor Necrosis Factor PA0 IFN=Interferon PA0 BM=Bone Marrow PA0 CFU-C=Committed Stem Cells
In Albeck et al., U.S. Pat. No. 4,764,461, which is incorporated herein by reference, there are described certain organic compounds of tellurium and selenium which are active in vitro and in vivo for the production of cytokines. These compounds are described as useful in the treatment of certain tumors, autoimmune diseases, immune diseases and infectious diseases. In Albeck et al., U.S. patent application, Ser. No. 07/172,642, filed Mar. 24, 1988, which is incorporated herein by reference, there are provided complexes of certain organic tellurium and selenium compounds with non-toxic complexing agents which have increased water solubility.
Sredni et al., U.S. patent application, Ser. No., 07/302,002, filed Jan. 26, 1989, which is incorporated by reference disclosed tellurium halides which are also useful in the practise of the invention.
It is also known that a variety of inflammatory and immuno-enhancing agents administered to mice prior to irradiation increases the number of animals which survive after lethal irradiation. The increase in survival is said to be associated with an earlier recovery of mature cells in the peripheral blood and hematopoietic colony-forming cells in the bone marrow and spleen. See, Smith et al., "Effects of Bacterial Endotoxin on the Occurrence of Spleen Colonies in Irradiated Mice," Radiat. Res., 27:389, 1966; Patchen et al., "Comparative Effects of Soluble and Particulate Glucans on Survival in Irradiated Mice," J. Biol. Response Mod., 5:45, 1986; Boggs et al., "Earlier Onset of Hematopoietic Differentiation after Expansion of the Endogenous Stem Cell Pool," Radiat. Res., 63:165, 1975; and Smith et al., "Effect of Endotoxin on the Kinetics of Hemopoietic Colony-Forming Cells in Irradiated Mice," Radiat. Res., 27:710, 1969, all of which are incorporated by reference.
Protection and/or recovery from the consequences of ionizing radiation has also been investigated at different cellular and molecular levels. DNA repair mechanisms and the chemical radioprotection afforded by thiol compounds are disclosed in Elkind, "Repair Processes in Radiation Biology," Radiat. Res. 100:425, 1984 and Nygaard et al., "Radioprotectors and Anticarcinogens," Academic Press, New York, 1983, both of which are incorporated herein by reference. Radioprotection has also been reported to be conferred by immunomodulatory substances. Numerous microbial compounds such as bacterial lipopolysacharide (LPS) muramyl dipeptide, Mycobacterium bovis strain BCG, and glucan are disclosed as having radioprotective effects when administered before irradiation. Behling, U. H., "Beneficial Effects of Endotoxin," Plenum Press, New York, 1983, incorporated herein by reference. Other studies have disclosed that large molecular weight compounds such as dextran-sulfate, carbon particles and polyacrylamide beads exhibit radioprotective effects when given 1-3 days before irradiation. See, Ross et al., "Radioprotection Conferred by Dextran-Sulfate Given Before Irradiation in Mice," Exp. Hematol., 14:147, 1988; Mori et al., "Reticuloendothellal System Blockade as an Effective Method of Radioprotection," Experimentia, 31:112, 1975; and Herodin et al., "Radioprotective Effect of an Acute Non-Specific Inflammation in Mice", Int. J. Radiat. Biol. 51:549, 1987, all of which are incorporated herein by reference.
Interleukin-1 (IL-1) has also been disclosed as a radioprotector. In Neta et al., "Radioprotection with IL-1: Comparison with Other Cytokines," Prog. IMM VI:900, 1986; Neta, et al., "Interleukin 1 Is a Radioprotector," J. Immunol. 136:2483, 1986; and Swartz et al., "Recovery of Hematopoietic Colony-Forming Cells in Irradiated Mice Pretreated with Interleukin-1," Exp. Hematol., 16:752, 1988, all of which are incorporated herein by reference, the authors demonstrated that a single injection of murine or human recombinant IL-1 alpha increased survival in lethally irradiated mice. In another study, the authors demonstrated that suboptimal doses of IL-1 in combination with non-protective doses of Granulocyte Macrophage colony stimulating factor (GM-CSF), Granulocyte colony stimulating factor (G-CSF) or Tumor necrosis factor (TNF) result in synergistic protection from radiation induced death. Neta et al., "Interdependence of the Radioprotective Effects of Human Recombinant Interleukin 1-a, Tumor Necrosis Factor and Granulocyte Colony-Stimulating Factor, and Murine Recombinant Granulocyte-Macrophage Colony Stimulating Factor," J. Immunol. 140:108, 1988.
It has now been surprisingly discovered that a certain class of synthetic organic derivatives of tellurium or selenium are capable of providing radio-protection from lethal effects of irradiation and significantly diminish hematopoietic damage caused by sublethal doses of irradiation.
Accordingly, it is a primary object of this invention to provide a method for reducing hematopoietic damage caused by irradiation which is based on the use of certain organic compounds of tellurium and selenium. It is also an object of this invention to provide a method for increasing survivability from lethal doses of irradiation which is based on the use of certain organic compounds of tellurium and selenium.